Lionel G. Nowak

The Timing of Information Transfer in the Visual System

The mammalian visual cortex is composed of a constellation of cortical areas that are interconnected by a dense network of corticocortical connections. Among those connections, it is usual to distinguish between feedforward and feedback connections. Feedforward connections carry information away from area V1 toward the parietal and the temporal lobes, whereas feedback connections carry impulses in the reverse direction (Salin and Bullier, 1995). It is becoming increasingly apparent that, despite its complexity, the visual system processes information very rapidly. The delay imposed by neuronal processing in the correction of visually guided movements is of the order of 100 msec (Rossetti, 1997). Recent results also suggest that visual recognition of complex scenes is possible within 100–200 msec (Thorpe el al., 1996).

Parallel versus serial processing: new vistas on the distributed organization of the visual system

Recent functional studies question the validity of the hierarchical model of organization for processing visual information in cortical areas. The results of these studies suggest that beyond the primary visual cortex (V1), information is not serially processed through successive cortical areas, but that it is simultaneously processed in several areas. The idea that visual information is functionally segregated into different, parallel channels as it circulates through V1 and V2 towards V4 and the middle temporal visual area is also challenged by recent studies that report a smaller degree of functional specialization within the visual areas than previously thought.

Role of synaptic and intrinsic membrane properties in short-term receptive field dynamics in cat area 17.

We examined the mechanisms through which the prolonged presentation of either a high-contrast stimulus or an artificial scotoma [equivalent to the stimulation of the receptive field (RF) surround] induces changes in the RF properties of neurons intracellularly recorded in cat primary visual cortex. Discharge and synaptic RFs were quantitatively characterized using bright and dark bars randomly flashed in various positions. Compared with the lack of stimulation (0% contrast for 15-30 s), stimulation with high-contrast sine-wave gratings (15-30 s) was followed by a strong reduction in gain and a weak but significant reduction in width of spike discharge RFs. These reductions were accompanied by a membrane potential hyperpolarization, a decrease of synaptic RF width, and varying changes of synaptic RF gain. Passive hyperpolarization by DC injection also produced significant reduction in the width and gain of discharge RF. Mimicking, in single neurons, high-contrast stimulation with high-intensity current injection also induced a membrane potential hyperpolarization, whose amplitude was correlated with discharge RF gain and width changes. Recovery from adaptation to high-contrast stimulation during the period of gray screen or scotoma presentation was associated with an increase in gain and discharge RF size. Stimulation of the RF surround with an artificial scotoma did not have any additional aftereffects over those of adaptation to a gray screen, indicating that the contraction and expansion of RF gain and size are attributable to intrinsic and synaptic mechanisms underlying adaptation and de-adaptation to strong visual stimuli.

Power-Law Input-Output Transfer Functions Explain the Contrast-Response and Tuning Properties of Neurons in Visual Cortex

We develop a unified model accounting simultaneously for the contrast invariance of the width of the orientation tuning curves (OT) and for the sigmoidal shape of the contrast response function (CRF) of neurons in the primary visual cortex (V1). We determine analytically the conditions for the structure of the afferent LGN and recurrent V1 inputs that lead to these properties for a hypercolumn composed of rate based neurons with a power-law transfer function. We investigate what are the relative contributions of single neuron and network properties in shaping the OT and the CRF. We test these results with numerical simulations of a network of conductance-based model (CBM) neurons and we demonstrate that they are valid and more robust here than in the rate model. The results indicate that because of the acceleration in the transfer function, described here by a power-law, the orientation tuning curves of V1 neurons are more tuned, and their CRF is steeper than those of their inputs. Last, we show that it is possible to account for the diversity in the measured CRFs by introducing heterogeneities either in single neuron properties or in the input to the neurons. We show how correlations among the parameters that characterize the CRF depend on these sources of heterogeneities. Comparison with experimental data suggests that both sources contribute nearly equally to the diversity of CRF shapes observed in V1 neurons.

Contrast adaptation contributes to contrast-invariance of orientation tuning of primate V1 cells.

Background Studies in rodents and carnivores have shown that orientation tuning width of single neurons does not change when stimulus contrast is modified. However, in these studies, stimuli were presented for a relatively long duration (e. g., 4 seconds), making it possible that contrast adaptation contributed to contrast-invariance of orientation tuning. Our first purpose was to determine, in marmoset area V1, whether orientation tuning is still contrast-invariant with the stimulation duration is comparable to that of a visual fixation. Methodology/Principal Findings We performed extracellular recordings and examined orientation tuning of single-units using static sine-wave gratings that were flashed for 200 msec. Sixteen orientations and three contrast levels, representing low, medium and high values in the range of effective contrasts for each neuron, were randomly intermixed. Contrast adaptation being a slow phenomenon, cells did not have enough time to adapt to each contrast individually. With this stimulation protocol, we found that the tuning width obtained at intermediate contrast was reduced to 89% (median), and that at low contrast to 76%, of that obtained at high contrast. Therefore, when probed with briefly flashed stimuli, orientation tuning is not contrast-invariant in marmoset V1. Our second purpose was to determine whether contrast adaptation contributes to contrast-invariance of orientation tuning. Stationary gratings were presented, as previously, for 200 msec with randomly varying orientations, but the contrast was kept constant within stimulation blocks lasting >20 sec, allowing for adaptation to the single contrast in use. In these conditions, tuning widths obtained at low contrast were still significantly less than at high contrast (median 85%). However, tuning widths obtained with medium and high contrast stimuli no longer differed significantly. Conclusions/Significance Orientation tuning does not appear to be contrast-invariant when briefly flashed stimuli vary in both contrast and orientation, but contrast adaptation partially restores contrast-invariance of orientation tuning.

Spatial and Temporal Features of Synaptic to Discharge Receptive Field Transformation in Cat Area 17

The aim of the present study was to characterize the spatial and temporal features of synaptic and discharge receptive fields (RFs), and to quantify their relationships, in cat area 17. For this purpose, neurons were recorded intracellularly while high-frequency flashing bars were used to generate RFs maps for synaptic and spiking responses. Comparison of the maps shows that some features of the discharge RFs depended strongly on those of the synaptic RFs, whereas others were less dependent. Spiking RF duration depended poorly and spiking RF amplitude depended moderately on those of the underlying synaptic RFs. At the other extreme, the optimal spatial frequency and phase of the discharge RFs in simple cells were almost entirely inherited from those of the synaptic RFs. Subfield width, in both simple and complex cells, was less for spiking responses compared with synaptic responses, but synaptic to discharge width ratio was relatively variable from cell to cell. When considering the whole RF of simple cells, additional variability in width ratio resulted from the presence of additional synaptic subfields that remained subthreshold. Due to these additional, subthreshold subfields, spatial frequency tuning predicted from synaptic RFs appears sharper than that predicted from spiking RFs. Excitatory subfield overlap in spiking RFs was well predicted by subfield overlap at the synaptic level. When examined in different regions of the RF, latencies appeared to be quite variable, but this variability showed negligible dependence on distance from the RF center. Nevertheless, spiking response latency faithfully reflected synaptic response latency.

Tetramisole and Levamisole Suppress Neuronal Activity Independently from Their Inhibitory Action on Tissue Non-specific Alkaline Phosphatase in Mouse Cortex

Tissue non-specific alkaline phosphatase (TNAP) may be involved in the synthesis of GABA and adenosine, which are the main inhibitory neurotransmitters in cortex. We explored this putative TNAP function through electrophysiological recording (local field potential ) in slices of mouse somatosensory cortex maintained in vitro. We used tetramisole, a well documented TNAP inhibitor, to block TNAP activity. We expected that inhibiting TNAP with tetramisole would lead to an increase of neuronal response amplitude, owing to a diminished availability of GABA and/or adenosine. Instead, we found that tetramisole reduced neuronal response amplitude in a dose-dependent manner. Tetramisole also decreased axonal conduction velocity. Levamisole had identical effects. Several control experiments demonstrated that these actions of tetramisole were independent from this compound acting on TNAP. In particular, tetramisole effects were not stereo-specific and they were not mimicked by another inhibitor of TNAP, MLS-0038949. The decrease of axonal conduction velocity and preliminary intracellular data suggest that tetramisole blocks voltage-dependent sodium channels. Our results imply that levamisole or tetramisole should not be used with the sole purpose of inhibiting TNAP in living excitable cells as it will also block all processes that are activity-dependent. Our data and a review of the literature indicate that tetramisole may have at least four different targets in the nervous system. We discuss these results with respect to the neurological side effects that were observed when levamisole and tetramisole were used for medical purposes, and that may recur nowadays due to the recent use of levamisole and tetramisole as cocaine adulterants.

Identification of altered brain metabolites associated with TNAP activity in a mouse model of hypophosphatasia using untargeted NMR‐based metabolomics analysis

Tissue non‐specific alkaline phosphatase (TNAP) is a key player of bone mineralization and TNAP gene (ALPL) mutations in human are responsible for hypophosphatasia (HPP), a rare heritable disease affecting the mineralization of bones and teeth. Moreover, TNAP is also expressed by brain cells and the severe forms of HPP are associated with neurological disorders, including epilepsy and brain morphological anomalies. However, TNAPs role in the nervous system remains poorly understood. To investigate its neuronal functions, we aimed to identify without any a priori the metabolites regulated by TNAP in the nervous tissue. For this purpose we used 1H‐ and 31P NMR to analyze the brain metabolome of Alpl (Akp2) mice null for TNAP function, a well‐described model of infantile HPP. Among 39 metabolites identified in brain extracts of 1‐week‐old animals, eight displayed significantly different concentration in Akp2−/− compared to Akp2+/+ and Akp2+/− mice: cystathionine, adenosine, GABA, methionine, histidine, 3‐methylhistidine, N‐acetylaspartate (NAA), and N‐acetyl‐aspartyl‐glutamate, with cystathionine and adenosine levels displaying the strongest alteration. These metabolites identify several biochemical processes that directly or indirectly involve TNAP function, in particular through the regulation of ecto‐nucleotide levels and of pyridoxal phosphate‐dependent enzymes. Some of these metabolites are involved in neurotransmission (GABA, adenosine), in myelin synthesis (NAA, NAAG), and in the methionine cycle and transsulfuration pathway (cystathionine, methionine). Their disturbances may contribute to the neurodevelopmental and neurological phenotype of HPP.

Prominent facilitation at beta and gamma frequency range revealed with physiological calcium concentration in adult mouse piriform cortex in vitro

Neuronal activity is characterized by a diversity of oscillatory phenomena that are associated with multiple behavioral and cognitive processes, yet the functional consequences of these oscillations are not fully understood. Our aim was to determine whether and how these different oscillatory activities affect short-term synaptic plasticity (STP), using the olfactory system as a model. In response to odorant stimuli, the olfactory bulb displays a slow breathing rhythm as well as beta and gamma oscillations. Since the firing of olfactory bulb projecting neurons is phase-locked with beta and gamma oscillations, structures downstream from the olfactory bulb should be driven preferentially at these frequencies. We examined STP exhibited by olfactory bulb inputs in slices of adult mouse piriform cortex maintained in vitro in an in vivo-like ACSF (calcium concentration: 1.1 mM). We replaced the presynaptic neuronal firing rate by repeated electrical stimulation (frequency between 3.125 and 100 Hz) applied to the lateral olfactory tract. Our results revealed a considerable enhancement of postsynaptic response amplitude for stimulation frequencies in the beta and gamma range. A phenomenological model of STP fitted to the data suggests that the experimental results can be explained by the interplay between three mechanisms: a short-term facilitation mechanism (time constant ≈160 msec), and two short-term depression mechanisms (recovery time constants <20 msec and ≈140 msec). Increasing calcium concentration (2.2 mM) resulted in an increase in the time constant of facilitation and in a strengthening of the slowest depression mechanism. As a result, response enhancement was reduced and its peak shifted toward the low beta and alpha ranges while depression became predominant in the gamma band. Using environmental conditions corresponding to those that prevail in vivo, our study shows that STP in the lateral olfactory tract to layer Ia synapse allows amplification of olfactory bulb inputs at beta and gamma frequencies.